A convenient synthesis of immunosuppressive agent FTY720 using the petasis reaction

Article abstract of DOI:10.1248/cpb.53.100

A convenient synthesis of immunosuppressive agent FTY720 (1) using the Petasis reaction was developed. 4-Octylbenzaldehyde (9) was converted into 1-ethenyl-4-octylbenzene (11) by two-step synthesis. Hydroboration of 11 using catecholborane and hydrolysis gave (E)-2-(4-octylphenyl)vinylboronic acid (4). The Petasis reaction of 4, dihydroxyacetone (3), and benzylamine following catalytic hydrogenation afforded FTY720 (1).

Full text of DOI:10.1248/cpb.53.100

100
Notes
Chem. Pharm. Bull. 53(1) 100—102 (2005)
Vol. 53, No. 1
A Convenient Synthesis of Immunosuppressive Agent FTY720 Using the
Petasis Reaction
Shigeo SUGIYAMA, Satoshi ARAI, Matsuri KIRIYAMA, and Keitaro ISHII*
Meiji Pharmaceutical University; 2–522–1 Noshio, Kiyose, Tokyo 204–8588, Japan.
Received July 22, 2004; accepted October 18, 2004; published online October 20, 2004
A convenient synthesis of immunosuppressive agent FTY720 (1) using the Petasis reaction was developed.
4-Octylbenzaldehyde (9) was converted into 1-ethenyl-4-octylbenzene (11) by two-step synthesis. Hydroboration
of 11 using catecholborane and hydrolysis gave (E)-2-(4-octylphenyl)vinylboronic acid (4). The Petasis reaction of
4, dihydroxyacetone (3), and benzylamine following catalytic hydrogenation afforded FTY720 (1).
Key words FTY720; immunosuppressive agent; Petasis reaction; boronic acid
A potent immunosuppressant ISP-I (myriocin, themozy- tion using (E)-2-phenylvinylboronic acid (6) and benzyl-
mocidin) was isolated from the culture broth of Isaria sin- amine in ethanol at room temperature (Chart 2). This reac-
clairii (ATCC24400), and this compound was structurally tion system gave (E)-2-benzylamino-2-styrylpropane-1,3-
simplified to give FTY720 (1),1—4) which also possesses con- diol (7) in 40%. A similar reaction using hydroxyacetone (5)
siderable immunosuppressive activity and is now being did not proceed, and we could not obtain aminoalcohol 8.
examined in clinical studies.5,6) FTY720 (1) is gaining wide The Petasis reaction has been applied for a-hydroxyalkanals,
interest in the transplantation field owing to its efficacy glyoxylic acid, and pyruvic acid as carbonyl components.10—12)
against autoimmune diseases, and graft and transplant rejec- We also showed here that dihydroxyacetone (3)10) was also a
tion without the deterrent side effects, such as generalized good carbonyl component for the Petasis reaction to afford
immunosuppression, typically seen with the widely utilized 2-substituted 1,3-propanediol derivatives.
drug cyclosporine.5) FTY720 (1), which is an analog of
On the basis of the result using 6 (Chart 2) we synthesized
sphingosine, is phosphorylated by sphingopsine kinase to FTY720 (1) via the Petasis reaction using (E)-2-(4-
give FTY720-P like sphingosine-1-phosphate (S1P),5,6) and octylphenyl)vinylboronic acid (4) (Chart 3). Following the
FTY720-P is a potent agonist at S1P receptors.5,6) The bio- literature protocol,13,14) 4-octylbenzaldehyde (9) was treated
logical effects of FTY720 on lymphocyte trafficking and the with triphenylphosphine and carbon tetrabromide in
growing evidence that these effects are mediated by the inter- dichloromethane to give 1,1-dibromostyrene 10. The reaction
action of FTY720-P with S1P receptors place S1P-mediated of n-butyl lithium with 10 in THF gave 1-ethenyl-4-octylben-
migration under the spotlight of therapeutics.5)
zene (11).13) The hydroboration15,16) of 11 using cathecolbo-
Due to the potent biological activity and simple structure rane in THF following hydrolysis15) gave 2-(4-octylphenyl)-
of FTY720 (1), the development of efficient routes to it has vinylboronic acid (4). The Petasis reaction using dihydroxy-
been the subject of synthetic interest. Some synthetic routes acetone (3), benzylamine and boronic acid 4 gave the desired
to 1 have been reported in 6.4% to 24% overall yield, includ- 2-amino-1,3-propanediol 2, and the subsequent catalytic
ing the alkylation of diethyl 2-acetamidomalonate with 2-(4- hydrogenolysis of 2 gave FTY720 (1).
octylphenyl)ethyl iodide1,4,7) or 2-bromo-1-(4-octylphenyl)-1-
In conclusion, we realized that dihydroxyacetone (3) was a
ethanone8) in the presence of bases and the bis-formylation of good carbonyl component for the Petasis reaction. Two
1-nitro-2-(4-octylphenyl)ethane by treatment with an aque- hydroxyl groups of dihydroxyacetone (3) appear to play an
ous formaldehyde solution in the presence of Amberlyst important role in the Petasis reaction. FTY720 (1) was syn-
A-21 resin.9)
thesized by a five-step synthesis from 4-octylbenzaldehyde
On the other hand, Petasis reported a Mannich-type cou- (9) in 28% overall yield. The key step was the Petasis reac-
pling reaction of vinyl- and arylboronic acids, amines and a-
hydroxyalkyl carbonyl compounds to afford aminoalco-
hols.10—12) It was envisaged that this methodology would
allow an efficient synthesis of FTY720 (1) via the synthetic
elaboration of the 2-amino-1,3-propanediol 2 derived from
the Petasis reaction of (E)-2-(4-octylphenyl)ethenylboronic
acid (4), dihydroxyacetone (3) and benzylamine (Chart 1).
For the primal study, we examined the reactivity of dihy-
droxyacetone (3) and hydroxyacetone (5) for the Petasis reac-
Chart 1
Fig. 1. FTY720 (1)
Chart 2
∗ To whom correspondence should be addressed. e-mail: ishiikei@my-pharm.ac.jp
© 2005 Pharmaceutical Society of Japan

January 2005
101
Chart 3
magnesium sulfate, filtered and concentrated in vacuo. The residue was
chromatographed on silica gel (hexane) to afford 11 (198 mg, 84%). Color-
less oil. 1H-NMR (400 MHz, CDCl3) d: 7.39 (2H, d, Jꢀ8.1 Hz, Ar), 7.12
(2H, d, Jꢀ8.1 Hz, Ar), 3.02 (1H, s, HCꢀC), 2.59 (2H, t-like m, ArCH2),
tion using dihydroxyacetone (3), benzylamine and 2-(p-
octylphenyl)vinylboronic acid (4).
Experimental
General All commercially available starting materials were used with- 1.59 (2H, m, ArCH2CH2), 1.29 (10H, m, CH2ꢁ5), 0.88 (3H, t-like m, Me).
out further purification. 4-Octylbenzaldehyde was purchased from Acros.
Melting points were measured with Yanaco MP-3 apparatus and are uncor-
rected. IR spectra were recorded on a Hitachi 215 spectrophotometer. NMR
spectra were obtained with JEOL JNM-GSX400 (1H-NMR: 400 MHz and
13C-NMR: 100 MHz) and JEOL JMS-DX302 (1H-NMR: 300 MHz) spec-
13C-NMR (CDCl3) d: 143.8 (C), 131.9 (CHꢁ2), 128.3 (CHꢁ2), 119.1 (C),
83.9 (CꢀC), 76.4 (CꢀC), 36.0 (CH2), 32.0 (CH2), 31.3 (CH2), 29.6 (CH2),
29.4 (CH2ꢁ2), 22.8 (CH2), 14.2 (Me). IR (film) cmꢂ1: 2930, 2860, 1515,
1465, 845, 830. EI-MS m/z: 214.1718 (Calcd for C16H22: 214.1723) MS m/z:
214 (Mꢃ, 68%), 115 (100). Anal. Calcd for C16H22: C, 89.66; H, 10.35.
trometers using tetramethylsilane as an internal standard. MS and high-reso- Found: C, 89.33; H, 10.54.
lution MS (HR-MS) were taken on a JEOL JMS-DX302 spectrometer. Col-
umn chromatography was performed with Merck silica gel 60 (230—400
mesh). Analytical TLC was performed on plates pre-coated with 0.25 mm
layer of silica gel 60 F254 (Merck).
(E)-2-Benzylamino-2-styrylpropane-1,3-diol (7) A mixture of (E)-2-
phenylvinylboronic acid (6, 100 mg, 0.68 mmol), dihydroxyacetone (3,
dimer, 61.5 mg, 0.68 mmol as the monomer) and benzylamine (72.9 mg,
0.68 mmol) in ethanol (7.0 ml) was stirred for 24 h at room temperature. The
reaction mixture was concentrated in vacuo. The residue was diluted with
(E)-2-Benzylamino-2-[2-(4-octylphenyl)ethenyl]propane-1,3-diol (2)
Cathecolborane (1 mol/l in THF, 4.33 ml, 4.33 mmol) was added one-shot to
a solution of 1-ethynyl-4-octylbenzene (11, 195 mg, 0.90 mmol) at room
temperature under argon. The mixture was stirred for 4 h at 80 °C. After
being cooled to room temperature the reaction mixture was diluted with
dichloromethane, and the aqueous layer was extracted three times with
dichloromethane. The extracts were combined, dried with magnesium, fil-
tered and concentrated in vacuo to give a crude (E)-2-(4-octylphenyl)vinyl-
boronic acid (4). Characteristic signals of 1H-NMR spectrum (300 MHz,
saturated aqueous sodium bicarbonate and extracted three times with ethyl CDCl3) d: 7.75 (1H, d, Jꢀ18.5 Hz, CHꢀC), 6.42 (1H, d, Jꢀ18.5 Hz,
acetate. The extracts were combined, dried with magnesium sulfate and con-
centrated in vacuo. The residue was chromatographed on silica gel
(hexane/ethyl acetate, 7 : 3) to give 7 (77.9 mg, 40%). This product was
recrystallized from tert-butyl methyl ether to afford colorless solid, which
was used for the spectral analysis. Colorless solid, mp 118—119 °C
CꢀCH).
A mixture of the crude 4, dihydroxyacetone (3, dimmer, 90.1 mg,
0.50 mmol) and benzylamine (98.5 mg, 0.91 mmol) in ethanol (9.1 ml) was
stirred for 1.5 d at room temperature. The reaction mixture was concentrated
in vacuo. The residue was diluted with saturated aqueous sodium bicarbon-
(tBuOMe). 1H-NMR (300 MHz, CDCl3) d: 7.25—7.40 (10H, m, Ar), 6.55 ate and extracted three times with chloroform. The extracts were combined,
(1H, d, Jꢀ16.6 Hz, PhCHꢀCH), 6.14 (1H, d, Jꢀ16.6 Hz, PhCHꢀCH), 3.76
dried with magnesium sulfate, and concentrated in vacuo. The residue was
chromatographed on silica gel (chloroform/methanol, 97 : 3) to give a mix-
(4H, s, CH2Oꢁ2), 3.74 (2H, s, PhCH2). 13C-NMR (CDCl3) d: 140.3 (C),
136.3 (C), 131.4 (CH), 129.2 (CH), 128.5 (CHꢁ2), 128.4 (CHꢁ2), 128.1 ture of 2 and cathecol. The mixture was purifed with partition with diethyl
(CHꢁ2), 127.8 (CH), 127.0 (CH), 126.2 (CHꢁ2), 65.7 (HOCH2ꢁ2), 61.5
ether/5% aqueous sodium hydroxide to give 2 (157 mg, 44%). Brown pow-
(NC), 46.6 (PhCH2). IR (KBr) cmꢂ1: 3470, 3300, 3520, 1450, 1065, 975,
der, mp 75—78 °C. 1H-NMR (400 MHz, CDCl3) d: 7.19—7.33 (7H, m, Ar),
750, 705. FAB-MS (glycerol), m/z: 284 (Mꢃ1). Anal. Calcd for C18H21NO2: 7.13 (2H, d, Jꢀ7.8 Hz, Ar), 6.50 (1H, d, Jꢀ16.8 Hz, CꢀCH), 6.07 (1H, d,
C, 76.30; H, 7.47; N, 4.94. Found: C, 76.21; H, 7.58; N, 4.75.
Jꢀ16.6 Hz, HCꢀC), 3.71 (6H, d-like m, Jꢀ10.5 Hz, HOCH2ꢁ2 and
1-(2,2-Dibromovinyl)-4-octylbenzene (10) Triphenylphosphine (2.41 g, NCH2Ph), 2.58 (2H, t, Jꢀ7.7 Hz, CH2Ar), 1.57—1.59 (2H, m, CH2), 1.26—
9.19 mmol) was added to a stirring solution of carbon tetrabromide (1.53 g,
4.61 mmol) in dichloromethane (11.5 ml) under argon at 0 °C. After 15 min,
4-octylbenzaldehyde (1.00 g, 4.58 mmol) was added rapidly. The mixture (CHꢁ2, Ar), 128.4 (CHꢁ2, Ar), 128.1 (CHꢁ2, Ar), 128.0 (CH, Ar), 127.0
1.29 (10H, m, CH2ꢁ5), 0.88 (3H, t, Jꢀ6.6 Hz, Me). 13C-NMR (CDCl3)
d: 142.8 (C, Ar), 140.3 (C, Ar), 133.7 (C, Ar), 131.3 (CH, Ar), 128.6
was stirred for 1 h at 0 °C, and the reaction mixture was slowly poured into
stirring hexane (180 ml). The supernatant liquid was decanted, and the sol-
vent was removed by using rotary evaporator. The triphenylphosphine oxide
was removed by filtration and washed with additional hexane. The solvent
was removed from the filtrate, and the residue was chromatographed on sil-
ica gel (hexane/ethyl acetate, 95 : 5) to give 10 (1.42 g, 83%). Colorless oil.
1H-NMR (400 MHz, CDCl3) d: 7.45 (2H, d, Jꢀ8.8 Hz, Ar), 7.44 (1H, s,
(CH, Ar), 126.1 (CHꢁ2, Ar), 65.8 (CH2), 61.3 (HNC), 46.6 (CH2), 35.8
(CH2), 32.0 (CH2), 31.5 (CH2), 29.6 (CH2), 29.38 (CH2), 29.36 (CH2ꢁ2),
22.8 (CH2), 14.2 (Me). IR (CHCl3) cmꢂ1: 2925, 2850, 1650, 1635, 1200.
FAB-MS (glycerol) m/z: 396.2906 (Calcd for C26H38NO2: 396.2902) MS
m/z: 396 (Mꢃ1)ꢃ.
2-Benzylamino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol Hydrochlo-
ride (FTY720), (1) A mixture of 2 (115 mg, 0.291 mmol) and 10% palla-
CHꢀC), 7.17 (2H, d, Jꢀ8.1 Hz, Ar), 2.58 (2H, t, Jꢀ7.8 Hz, ArCH2), 1.60 dium carbon (115 mg) in ethanol (10 ml) with 10% aqueous hydrochloric
(2H, m, ArCH2CH2), 1.27 (10H, m, CH2ꢁ5), 0.88 (3H, t Jꢀ6.6 Hz, CH3). acid (0.12 ml) was stirred for 12 h at room temperature in atmosphere of hy-
13C-NMR (CDCl3) d: 143.5 (C), 136.6 (CHꢀC), 132.5 (C), 128.3 (CHꢁ2), drogen. The reaction mixture was filtered through a pad of Celite, and the
128.2 (CHꢁ2), 35.9 (CH2), 32.0 (CH2), 31.3 (CH2), 29.6 (CH2), 29.43 filtrate was concentrated in vacuo to afford FTY720 (1) (90 mg, 90%). Yel-
(CH2), 29.36 (CH2), 22.8 (CH2), 14.3 (CH3). IR (film) cmꢂ1: 2930, 1620, low powder, mp 105—108 °C (decompose). 1H-NMR (300 MHz, DMSO-d6)
1470. EI-MS m/z: 372.0086 (Calcd for C16H22Br2: 372.0089) MS m/z: 376 d: 7.91 (3H, br s), 7.10 (4H, s, Ar), 5.38 (2H, br s), 3.52 (4H, d, Jꢀ4.2 Hz,
(Mꢃ4, 48%), 374 (Mꢃ2, 100%), 372 (Mꢃ, 50%).
CH2Oꢁ2), 2.50—2.60 (4H, m, CH2ꢁ2), 1.75—1.81 (2H, m, CH2), 1.53
(2H, br s, CH2), 1.24 (10H, m, CH2ꢁ5), 0.85 (3H, t, Jꢀ6.3 Hz, Me);
(400 MHz, CD3OD) d: 7.14 (2H, d, Jꢀ8.0 Hz, Ar), 7.08 (2H, d, Jꢀ8.0 Hz,
Ar), 4.86 (4H, s, CH2Oꢁ2), 2.61—2.65 (2H, m, ArCH2), 2.55 (2H, t,
Jꢀ7.6 Hz, CCH2), 1.92—1.97 (2H, br s, CH2), 1.57 (2H, br s, CH2), 1.28—
1.30 (10H, m, CH2ꢁ5), 0.89 (3H, t, Jꢀ6.8 Hz, Me). 13C-NMR (DMSO-d6)
d: 139.4 (C, Ar), 138.5 (C, Ar), 127.9 (CHꢁ2, Ar), 127.7 (CHꢁ2, Ar), 60.9
(CH2Oꢁ2), 60.1 (NC), 34.7 (CH2), 33.2 (CH2), 31.2 (CH2), 31.0 (CH2),
28.8 (CH2), 28.6 (CH2ꢁ2), 27.9 (CH2), 22.0 (CH2), 13.9 (Me); (CD3OD) d:
141.6 (C, Ar), 139.3 (C, Ar), 129.3 (CHꢁ2, Ar), 128.9 (CHꢁ2, Ar), 62.5
1-Ethynyl-4-octylbenzene (11) n-Butyl lithium (1.58 mol/l in hexane,
1.54 ml, 2.42 mmol) was added dropwise to a solution of 1-(2,2-dibro-
movinyl)-4-octylbenzene (10, 412 mg, 1.10 mmol) in THF (5.5 ml) at
ꢂ78 °C. The resulting mixture was stirred for 1 h at ꢂ78 °C and then for 2 h
at room temperature. A mixture of saturated aqueous ammonium chloride/
water (4 : 1) was added to the reaction mixture, and the mixture was stirred
for 1 h. The reaction mixture was concentrated in vacuo, and the residue was
diluted with dichloromethane and washed with water. The aqueous layer was
extracted with dichloromethane. The extracts were combined, dried with

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Vol. 53, No. 1
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1231 (2004).
(CH2O, ꢁ2), 62.0 (C), 36.5 (CH2), 34.7 (CH2), 33.0 (CH2), 32.7 (CH2), 30.5
(CH2), 30.4 (CH2), 30.3 (CH2), 29.7 (CH2), 23.7 (CH2), 14.5 (Me). FAB-MS
(glycerol) m/z: 308.2604 (Calcd for C19H35ClNO2–HCl: 308.2591) MS m/z:
308 (Mꢃ1ꢂHCl)ꢃ.
7) Seidel G., Laurich D., Fürstner A., J. Org. Chem., 69, 3950—3952
(2004).
8) Durand P., Peralba P., Sierra F., Renaut P., Synthesis, 2000, 505—506
(2000).
Acknowledgment The authors wish to thank the staff of the Analysis
Center of Meiji Pharmaceutical University for performing mass spectra
(Miss T. Koseki).
9) Kalita B., Barua N. C., Bezbarua M., Bez G., Synlett, 2001, 1411—
1414 (2001).
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